A clinical trial for psoriasis with novel single-cell genomic techniques to understand regulatory immunity behind long-term disease remission off drug induced by short-term IL-23 inhibition
使用新型单细胞基因组技术进行银屑病临床试验,以了解短期 IL-23 抑制诱导的药物长期疾病缓解背后的调节免疫
基本信息
- 批准号:10340103
- 负责人:
- 金额:$ 16.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-18 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:AnatomyAntibodiesAntigen-Presenting CellsBiologicalBiological MarkersBiological ProductsBiopsyBiopsy SpecimenCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell CommunicationCellsChromatinClinicalClinical TrialsDataDendritic CellsDigestionDiseaseDisease ProgressionDisease remissionDoseEnzymesEpidermisFOXP3 geneGene ExpressionGenomicsGoalsHourHumanImmuneImmune System DiseasesImmune ToleranceImmune responseImmunityImmunobiologyInjectionsKLRB1 geneLesionMachine LearningMentorsMessenger RNAMicrofluidicsMolecularNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNatural Killer CellsOutcomePathogenicityPathologicPatientsPharmaceutical PreparationsPhasePhenotypePsoriasisPublic HealthRecurrenceRegulationRegulatory T-LymphocyteResearchSkinT-LymphocyteTechniquesTestingbasecell typechronic inflammatory diseaseclinical applicationcombinatorialcytokinedrug clearancegenetic signaturegenomic datahealthy volunteerindexinginnovationinterleukin-23keratinocytemelanocytenovelpredictive modelingpreventprogramsrestorationsingle-cell RNA sequencingskin disordertranscriptometranscriptome sequencing
项目摘要
Although highly effective, biologics targeting IL-23/Th17 axis should be continuously injected to
suppress recurrence of psoriasis. My long-term goal is to cure psoriasis without recurrence guided by
personal immune tolerance. The overall objectives in this application are to (i) identify regulatory immune
cell interactions induced by anti-IL-23p19 antibody administration in the skin of patients whose psoriasis
is cleared without recurrence and (ii) develop pre-treatment predictive models for psoriasis patients that
anticipate disease recurrence after short-term anti-IL-23p19 antibody injection. The central hypothesis is
that IL-23p19 inhibition promotes regulatory immune cells in psoriasis patients whose disease is cleared
without recurrence, and their pre-treatment single-cell immune signatures are different from those of patients
whose disease recurs. The rationale for this project is that molecular evidence of immune tolerance
induction by IL-23p19 inhibition in human skin is likely to offer a strong clinical framework whereby new
strategies to prevent recurrence of chronic inflammatory diseases can be developed. The central hypothesis
will be tested by pursuing two specific aims: 1) Testing the hypothesis that regulatory immune cell
interactions are promoted by short-term anti-IL-23p19 antibody administration in the skin of psoriasis patients
whose disease becomes clear without recurrence; and 2) Developing predictive models with pretreatment
skin biopsy single-cell genomic data that anticipate long-term disease clearance off drug after
short-term anti-IL-23p19 antibody administration. To achieve the specific aims, we have recently developed
two innovative complementary single-cell approaches to obtain gene expression profiles of heterogeneous
immune cells from psoriasis and control skin without enzyme digestion. The first single-cell experimental
approach is microfluidic partitioning of emigrating cells from human skin after 48-hour incubation
in culture medium without enzyme digestion, which empowers single-cell transcriptomic profiling of
heterogeneous immune cells and keratinocytes in different layers of epidermis under ex vivo condition.
The second single-cell experimental approach is Combinatorial indexing RNA sequencing, developed by
the co-mentor of the proposal, which enables co-profiling transcriptome and single-cell chromatin accessibility.
At the completion of the proposed research, our expected outcomes are to have novel single-cell
genomic techniques to study immune cell interactions in human skin, defined single-cell gene signatures
of regulatory immune cells that are promoted by anti-IL-23p19 antibody administration in psoriasis skin,
and the ability to elucidate how pathologic immunity is suppressed at the single-cell level by highly effective
biologics. We also expect to have pre-treatment biomarkers that can predict long-term disease clearance
off drugs after short-term anti-IL-23p19 antibody administration.
尽管高效,但针对IL-23/Th17轴的生物制剂应持续注射到
抑制牛皮癣的复发。我的长期目标是治愈牛皮癣而不复发
个人免疫耐受性。本申请的总体目标是:(I)确定监管免疫
抗IL-23p19抗体在银屑病患者皮肤中诱导的细胞相互作用
被清除而不会复发以及(Ii)为牛皮癣患者开发治疗前预测模型
预测短期注射抗IL-23p19抗体后的疾病复发。中心假设是
抑制IL-23p19促进银屑病患者病情好转的调节性免疫细胞
无复发,治疗前的单细胞免疫特征与患者不同
他的病会复发。这个项目的基本原理是免疫耐受的分子证据
抑制IL-23p19在人类皮肤中的诱导可能提供一个强大的临床框架,使新的
可以制定预防慢性炎症性疾病复发的策略。中心假说
将通过追求两个具体目标进行测试:1)测试调节性免疫细胞
短期应用抗IL-23p19抗体可促进银屑病患者皮肤的相互作用
谁的疾病变得明确而不会复发;以及2)通过预处理开发预测模型
皮肤活检单细胞基因组数据预测药物治疗后长期疾病清除
短期应用抗IL-23p19抗体。为了实现特定的目标,我们最近开发了
两种创新的互补单细胞方法获取异质性基因表达谱
来自牛皮癣的免疫细胞和对照皮肤,无需酶消化。第一个单细胞实验
方法是微流控分离培养48小时后的人皮肤移行细胞
在没有酶消化的培养液中,这使得单细胞转录图谱
体外培养条件下,异质免疫细胞和角质形成细胞分布于不同层次的表皮。
第二种单细胞实验方法是组合索引RNA测序,由
该提案的共同指导者,使联合分析转录组和单细胞染色质的可及性成为可能。
在拟议的研究完成后,我们的预期结果是拥有新的单细胞
研究人体皮肤免疫细胞相互作用的基因组技术,定义了单细胞基因特征
在银屑病皮肤中,由抗IL-23p19抗体促进的调节性免疫细胞,
以及阐明病理免疫是如何在单细胞水平上被高度有效地抑制的能力
生物制品。我们还希望有可以预测长期疾病清除的治疗前生物标记物。
停药后短期给予抗IL-23p19抗体。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Jaehwan Kim其他文献
Jaehwan Kim的其他文献
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{{ truncateString('Jaehwan Kim', 18)}}的其他基金
A clinical trial for psoriasis with novel single-cell genomic techniques to understand regulatory immunity behind long-term disease remission off drug induced by short-term IL-23 inhibition
使用新型单细胞基因组技术进行银屑病临床试验,以了解短期 IL-23 抑制诱导的药物长期疾病缓解背后的调节免疫
- 批准号:
10685945 - 财政年份:2022
- 资助金额:
$ 16.89万 - 项目类别:
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